Inhibition of myo-inositol transport causes acute renal failure with selective medullary injury in the rat.
Myo-inositol is a major compatible osmolyte in the renal medulla that is accumulated under hypertonic conditions via the Na+/myo-inositol cotransporter (SMIT). We have recently reported that SMIT is predominantly present in the thick ascending limb of Henle (TAL) and is strongly induced by acute NaCl loading, suggesting an important role of myo-inositol in this nephron segment. In the present study, we sought to examine in vivo effects of inhibition of myo-inositol transport using a transport inhibitor, 2-O, C-methylene-myo-inositol (MMI). Intraperitoneal injection of MMI caused acute renal failure in the rats. Serum creatinine and urea nitrogen were significantly increased 12 hours after MMI injection. Morphologic study revealed that the tubular cells were extensively injured in the outer medulla. A considerable number of the tubular cells were injured in the cortex as well. Immunohistochemical study for Tamm-Horsfall protein (THP), which was used for identification of the TAL cells, showed that THP-positive cells were predominantly injured. The tubular injury apparently appeared to worsen when high concentration of NaCl was injected with MMI. Administration of myo-inositol prevented acute renal failure and improved the tubular injury after MMI injection. Furthermore, supplementation of betaine, another osmolyte in the TAL cells, partially prevented the toxic effects of MMI. These results suggest that myo-inositol play a crucial role in the TAL regarding osmoregulation of the cells.
Kitamura
H
H
First Department of Medicine, Osaka University School of Medicine, Japan.
Yamauchi
A
A
Sugiura
T
T
Matsuoka
Y
Y
Horio
M
M
Tohyama
M
M
Shimada
S
S
Imai
E
E
Hori
M
M
D058186:Acute Kidney Injury / Q000209:etiology*; D000818:Animals; D001692:Biological Transport; D002352:Carrier Proteins / Q000502:physiology; D006360:Heat-Shock Proteins / Q000502:physiology; D007294:Inositol / Q000378:metabolism*; D007679:Kidney Medulla / Q000473:pathology*; D008138:Loop of Henle / Q000502:physiology; D008297:Male; D008565:Membrane Proteins; D009088:Mucoproteins / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride / Q000378:metabolism; D027981:Symporters; D058949:Uromodulin; D014882:Water-Electrolyte Balance
D002352:Carrier Proteins; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D009088:Mucoproteins; D012333:RNA, Messenger; D027981:Symporters; C548612:UMOD protein, human; C548614:Umod protein, rat; D058949:Uromodulin; C073884:SLC5A3 protein, human; D012965:Sodium Chloride; D007294:Inositol